Receptors for the Fc domain of IgG (FcγRs) amongst other factors are known to play a role in the regulation of the immune system. Currently, three classes of FcγRs are distinguished on cells of the immune system: the high-affinity receptor FcγRI (CD64), capable of binding monomeric IgG; the low-affinity receptors FcγRII (CD32) and FcγRIII (CD16), which interact preferentially with complexed IgG. Although these receptors show overlapping binding patterns for IgG subclasses, they vary in their cellular effector functions. FcγRI, FcγRIIa and FcγRIIIa are activating receptors, characterised by the presence of an immunoreceptor tyrosine-based activation motif immunoreceptor tyrosine-based activation motif (ITAM), either in the cytoplasmic domain of the receptor (FcγRIIa) or associated with the receptor as an accessory signalling subunit (γ and/or β chains associated with FcγRI and FcγRIIIa). By contrast, FcγRIIb is an inhibitory receptor, containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. A marked exception to this dichotomy is FcγRIIIb; this receptor is linked to the outer leaflet of the plasma membrane by a glycosyl phosphatidylinositiol (GPI) anchor and does not contain or associate with ITAMs or ITIMs. There is presently no homolog described for FcγRIIa or FcγRIIIb in mice.
Whilst FcγR:Ig interactions are important effector systems in immunity, their role in autoimmune disease is uncertain. In humans the major inflammatory cells—macrophages, neutrophils, eosinophils and mast cells are known to express FcR receptors, including FcγRI, FcγRIIa, FcγRIIb, and FcγRIIIa, or FcγRIIIb.
FcγRIIa is present only in humans and higher primates, so there is no equivalent in mice or other rodents. The receptor is of particular interest because of the dependence of other Fc receptors on this receptor for their signal transduction and cell activating properties (Chuang et al. 2000). FcγRIIa can be expressed in transgenic mice with the same expression pattern as in humans (McKenzie et al. 1999). Thus human FcγRIIa can interact appropriately with intracellular signalling pathways in the mouse and appear normal in all respects, although changes in cross-species regulation in transgenics should always be considered in interpreting results. Transgenic mice expressing the human FcγRIIa have shown that this receptor is a major factor in platelet destruction in immune thrombocytopenia (McKenzie et al. 1999). The role of FcR receptors in inducing cell activation is known for in vitro systems, but their role in inflammation in vivo is less understood and has recently been studied, as described herein.
As a result of the use of gene knock out animals, the scientific and medical communities believe that the principal receptor involved in the induction of inflammation in vivo is FcγRIII (also known as CD16). Many studies in the literature indicate this and this has formed part of recent text book descriptions of immune complex induced inflammation. It was therefore very surprising that transgenic mice expressing the human FcγRIIa are highly sensitive to immune complex induced inflammation, also spontaneously develop inflammation in a variety of organs and tissues characteristic of a number of autoimmune diseases such as rheumatoid arthritis, systemic lupus erthemotosus (SLE), induced autoimmune disease such as glomerular basement membrane nephritis. Moreover, mice that develop these surprising inflammatory sensitivities are also useful for testing drugs.
However, no studies have examined the role of this FcR in autoimmune disease, such as SLE, arthritis or any other immune complex disorders, for example, the role of this Fc receptor in immune complex or antibody induced inflammation associated with autoimmune diseases. Inflammation in these diseases can include vasculitis, lupus nephritis and arthritis. Inflammation can also occur in diseases not necessarily classified as autoimmune such as infectious arthritis, in renal diseases such as mixed cryoglobulinemia, bacterial infections, in malignant diseases, in gastrointestinal diseases, complement deficiencies and in a number of miscellaneous conditions.
Accordingly, there remains a need for providing effective methods and models for autoimmune disease and methods for identifying compounds that can reduce aberrant immune activity, inflammation and disease processes. The surprising observation of the increased sensitivity to collagen induced arthritis in the transgenic mice whose genetic make up is composed of genes from otherwise genetically resistant mice, together with the observation of a spontaneous autoimmune disease, including arthritis was surprising. More surprising was that on further analysis of the transgenic animals, evidence of spontaneous autoimmunity and inflammation in tissues was evident. Inflammation in kidneys and in lungs occurred in many, though not all mice and histological examination of the joints showed features characteristic of rheumatoid arthritis, i.e. bone destruction and panus formation or features more characteristic of arthritis associated with diseases such as SLE where panus does not form. It would appear therefore that the presence of human FcγRIIa receptor in these mice allows the development of quite different inflammatory processes in different tissues that make up different clinical diagnoses.